PROJECT SUMMARY There is substantial evidence that soluble A? oligomers are neurotoxic1-5 and that impaired clearance of soluble A? is a critical pathologic mechanism in late-onset AD, a concept supported by the observation of decreased passage of A? into the cerebrospinal fluid (CSF) in AD6 and the decreased levels of A? in the CSF of AD patients7,8,9,10. The mechanisms for clearance of extracellular A? from the brain are multiple11 and include local enzymatic degradation12, transport across the blood brain barrier (BBB)13-16, or via the CSF17. The relative contributions of these various systems to A? clearance are not fully understood, although the BBB system appears to be predominant. However, recently, the glymphatic system has been implicated in this process, possibly in addition to BBB mechanism15,16. The glymphatic system18,19 is proposed as a brain waste clearance pathway consisting of perivascular tunnels lined by astrocytes that drain into CSF and eventually into cervical lymphatic nodes20-22. This system allows for the elimination of soluble proteins and metabolites from the central nervous system and it may be implicated in A? clearance and the development of AD11. The clearance efficiency of the glymphatic system depends on CSF flow, cerebrovascular pulsation, and the aquaporin-4 (AQP4) water channels of perivascular astrocytes23. In mice, the efficiency of the glymphatic pathway appears compromised in aging due to impairment of AQP4 dependent bulk flow23. The role of the glymphatic system in the clearance of A? and its relevance to AD is based mostly on studies in rodents24,23,25, which is one of the reasons why it remains controversial26. Therefore, the relevance of the glymphatic system to AD needs to be examined in the human brain, which is the overall goal of this proposal. Moreover, we believe that the best time to conduct this examination is before and during the early stages of A? deposition. To this end, we have available a large number of human postmortem brains from individuals 30 to 65 years of age which are fully characterized for AD lesions and tissue integrity, and genotyped for ApoE. The exploratory and observational studies proposed here are the basis for future mechanistic examination of the glymphatic system and its relevance to AD to be conducted in cultured cells and tissues, and animal models.